Prevalence and Humanistic Impact of Potential Misdiagnosis of Bipolar Disorder Among Patients With Major Depressive Disorder in a Commercially Insured Population

BACKGROUND: Patients with bipolar disorder typically present to physicians in the depressed rather than the manic or hypomanic phase of illness. Because the depressive episodes in bipolar disorder may be indistinguishable from those in major depressive disorder (MDD), misdiagnosis may occur. OBJECTIVES: To estimate from administrative claims data and a telephone survey the prevalence of potential misdiagnosis of bipolar disorder among patients with MDD and the humanistic (health-related quality of life [HRQOL] and disability) effects associated with misdiagnosis in a managed care setting. METHODS: Administrative claims data were used to identify patients with medical claims for MDD from a database of 9 million members of commercial health plans from 3 U.S. regions. The inclusion criteria were as follows: (a) adults aged 18 years or older; (b) at least 2 medical claims, including a primary or secondary diagnosis of MDD: ICD-9-CM codes 296.2x (MDD, single episode), 296.3x (MDD, recurrent episode), or 311 (depressive disorder, not classified elsewhere) during an identification period from January 1, 2000, through March 31, 2004 (study intake period); (c) at least 12 months of pre-index and 12 months of post-index plan eligibility; and (d) active enrollment through March 31, 2005. The index date was defined as the date of the first claim for MDD during the identification period. Patients with ICD-9-CM codes for bipolar disorder at any time throughout the study period (January 1, 2000, through March 31, 2005) were excluded from this cohort. This cohort was targeted for a telephone survey that was conducted from August 1 through October 30, 2006. From the telephone survey sampling frame of 5,777, a total of 1,360 interviews were completed for a response rate of 23.5%. Respondents were screened for potential bipolar disorder using the Mood Disorder Questionnaire (MDQ). The Medical Outcomes 12-Item Short Form Survey (SF-12), Version 2, a widely used and validated instrument that assesses health-related functioning, and the Sheehan Disability Scale (SDS), which measures depression-related disability, were administered to a convenience subsample of 112 survey respondents to collect HRQOL and disability information, respectively. RESULTS: Of 1,360 adult patients aged 18 years or older with a diagnosis of MDD but without a medical claim for diagnosis of bipolar disorder, 94 (6.9%) screened positive for bipolar disorder on the MDQ. More patients with a positive screen for bipolar disorder reported lifetime histories of obsessive compulsive disorder (24.5% vs. 8.2%, P less than 0.001), psychotic disorders or hallucinations (9.6% vs. 2.4%, P less than 0.001), suicidal ideation (61.7% vs. 29.4%, P less than 0.001), and drug abuse (34.0% vs. 11.1%, P less than 0.001) than did patients with a negative screen for bipolar disorder. In the subgroup of patients who completed the SF-12 and SDS, patients with a positive screen for bipolar disorder (n = 33) had lower scores (i.e., greater impairment) on the social functioning, role emotional, and overall mental component summary scales of the SF-12 than did patients with a negative screen for bipolar disorder (n = 79, P less than 0.001), but did not significantly differ on the physical component summary scale. Patients with a positive screen for bipolar disorder on the MDQ were more likely than patients who screened MDQ-negative to report severe depression-related impairment (scores of 7 and higher on the SDS scale) with work life (54.5% vs. 24.1%, respectively, P = 0.002), social life (66.7% vs. 39.2%, P = 0.008), and family life (66.7% vs. 34.2%, P = 0.002) on the SDS. CONCLUSIONS: In this study of patients carrying medical claims for a diagnosis of MDD in their administrative claims data, approximately 7% screened positive for bipolar disorder on a validated self-report assessment instrument. Patients with MDD who screened positive for bipolar disorder reported poorer HRQOL and disability scores than did patients with MDD who screened MDQ-negative. These findings may encourage interventions for appropriate screening, diagnosis, and management of potentially misdiagnosed bipolar disorder patients.

• Misdiagnosis of bipolar disorder is common. In a survey of support group participants diagnosed with bipolar disorder, 69% reported initial misdiagnosis by the first physician from whom they sought treatment, and misdiagnosed patients reported seeing a mean of 4 physicians before being diagnosed with bipolar disorder. • Previous studies of the misdiagnosis of bipolar disorder were conducted in the clinical/outpatient setting. However, the rate of misdiagnosis among commercially insured patients, who may be "healthier" than patients recruited from clinical/outpatient service centers, is unknown.
What is already known about this subject B ipolar disorder, a chronic psychiatric illness with a variable course, affects between 1% and 4.4% of the U.S. population 1,2 and costs more than $7 billion in direct medical costs and $38 billion in indirect costs (1991 values). 3 According to the World Health Organization, bipolar disorder was among the top 10 causes of disability in the world in 2000 4 and was associated with significant impairment of a patient's health-related quality of life (HRQOL) even after symptomatic recovery. 5,6 Patients with bipolar disorder suffer high rates of unemployment 7 (up to 60%) or occupational difficulties 8,9 (up to 88%), and twothirds of patients report difficult family relationships. 9 Moreover, misdiagnosis of bipolar disorder is common. 7,10 In Hirschfeld et al.'s survey of support group participants diagnosed with bipolar disorder, 69% reported initial misdiagnosis by the first physician from whom they sought treatment, and misdiagnosed patients reported seeing a mean of 4 physicians before being diagnosed with bipolar disorder. 7 Without proper treatment, the symptoms of bipolar disorder (including suicide attempts) tend to increase in frequency and severity 11 and are less easy to manage with pharmacological intervention. 12 Accurate diagnosis necessitates a medical history from the patient and family or friends, 7 and the patient-rated Mood Disorder Questionnaire (MDQ) has been shown to be a useful screening tool for bipolar disorder. [13][14][15] In particular, differentiation of bipolar disorder from major depressive disorder (MDD) is essential for the appropriate management of the patient's condition, 16 and an analysis of administrative claims data found an association between undiagnosed bipolar disorder and higher total all-cause medical costs. 17 This study was undertaken to document the rate of positive screens for bipolar disorder among an MDD population in a managed care setting. The impact of misdiagnosis on HRQOL and depression-related disability was evaluated. Quantifying potential bipolar disorder misdiagnosis among the MDD population may help to optimize the identification and therapeutic management of these patients and may result in better patient outcomes.

■■ Methods
This study was a retrospective analysis of administrative claims, with cross-sectional diagnostic and HRQOL evaluations performed on a subset of patients. The study used data from 3 geographically dispersed health plans located in the southeastern, western, and midwestern regions of the United States, consisting of approximately 9 million commercially insured members. Patients enrolled in Medicare or Medicaid were not included in the study. The claims dataset included medical (inpatient, outpatient, and emergency room [ER] visits) and pharmacy encounters, as well as eligibility files. The study protocol and the survey instrument were sent to Quorum Review Inc., an independent institutional review board (IRB), for approval and to receive a Partial Waiver of Authorization under the terms of the Health Insurance Portability and Accountability Act (HIPAA) to use patient-level data for purposes of contacting patients for the survey. The study protocol included involvement of an external vendor to conduct the survey, which was approved by the IRB. All researchers handling protected health information were authorized to do so per company guideline and policies, and all study materials were treated with confidentiality.

Patient Identification
The study population was identified in 2 phases-first through examination of data from administrative claims, and then by telephone survey, conducted in a subset of patients ( Figure 1).

Identification of Survey Sample
Adults aged 18 years or older with (a) at least 2 medical claims, including a primary or secondary diagnosis of MDD with dates of service between January 1, 2000, and March 31, 2004 (study identification period); (b) at least 12 months of pre-index and 12 months of post-index plan eligibility; and (c) active enrollment through March 31, 2005, were selected for the claims analysis. The index date was defined as the date of the first claim for MDD during the identification period. Patients were required to have at least 2 medical claims for MDD because we wanted to select a patient population that had a chronic form of depression. MDD diagnostic codes were based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM; Table 1). Patients with ICD-9-CM codes for bipolar disorder at any time during the entire study period (January 1, 2000, through March 31, 2005) were excluded from this cohort. Telephone Survey: Bipolar Disorder Screening, Health Functioning, and Impairment Assessment A minimum sample of approximately 1,300 completed surveys was needed to assess the screen positive rate for bipolar disorder using the MDQ. Using a standard confidence interval formula, the sample size required to estimate the prevalence of misdiagnosis within ± 2.75% around the true population misdiagnosis rate was approximately 1,300 completed surveys. 18 The research question was to assess the unknown screen positive rate in the general population by conducting the survey on a sample of patients with MDD.
The surveys were initiated in August 2005 and were conducted by telephone survey interviewers who were experienced in health services research and trained extensively on the survey script. Because we wanted the survey sample to have the same age, gender, and regional distribution as that of the master calling list, we interviewed patients after categorizing them into different strata based on age, gender, and regions, then randomly selected patients from each stratum for completing the survey. The structured telephone survey was administered by placing calls at various times throughout the week. To confirm the MDD diagnoses that had been used to select the sample, prospective respondents were asked during the screening process whether they had ever been told by a physician that they had depression.
Demographics (age, gender, employment status, and marital status), self-reported lifetime history of mental health conditions, such as suicidal ideation ("thoughts about suicide"); obsessive compulsive disorder; psychotic symptoms ("psychotic disorder, hallucinations, or delusions"); and lifetime history of lifestyle characteristics, such as alcohol use and substance abuse, were collected from the entire group of 1,360 patients through this survey. Respondents who completed this portion of the survey were paid $25 for their time. A convenience sample subset of patients (n = 112) was selected from among the 1,360 patients who completed the MDQ screening portion of the survey and 2 additional self-report instruments were administered to the subsample during the same interview: the Medical Outcomes Study 12-Item Short Form Health Survey (SF-12), Version 2, 19,20 a widely used and validated instrument that assesses health-related functioning, and the Sheehan Disability Scale (SDS), a measure of depression-related disability. 21,22 Patients who were selected and agreed to complete the SF-12 and the SDS were compensated with an additional $10.

MDQ
The MDQ, a self-report screening instrument for bipolar I and II disorder, has been validated in adults across a wide array of settings. [14][15][16] The questionnaire consists of 13 Yes/No items assessing lifetime history of disturbances in mood, selfconfidence, mental functioning, energy, social functioning, interest in sex, and risk behavior. The MDQ also assesses the impact of these symptoms on functioning (e.g., "like being unable to work; having family, legal, or money troubles; getting into arguments or fights") on a 4-point scale (no problem, minor problem, moderate problem, or serious problem). A positive MDQ screen is defined as a positive response for greater than or equal to 7 of the 13 symptom items, co-occurrence of "several" symptoms, and moderate or serious symptom impact. 13

SF-12
The SF-12 is a validated, reliable screening tool for assessing HRQOL on a 5-point scale. 19,20 The SF-12 measures the domains of physical functioning, role physical, bodily pain, and general health, and vitality, which constitute the physical component scale (PCS). The SF-12 also measures social functioning, role emotional, and mental health domains that constitute the mental component scale (MCS).

SDS
The SDS is a 10-point self-rated assessment tool with demonstrated validity and reliability in psychiatric populations. 21,22 SDS items measure depression-related impairments in work, social, and family life (reported as item scores and summary scores), as well as depression-related absenteeism and reduced efficiency.

Prevalence Outcomes
The prevalence of potentially misdiagnosed bipolar disorder among patients diagnosed with MDD was derived by calculating the proportion of patients who screened positive for bipolar disorder on the MDQ and dividing by the total number of patients with MDD who completed the survey.

Burden of Disease: Humanistic Outcomes
HRQOL and disability/impairment were evaluated using summary scale and domain scores from the SF-12 and SDS item and composite scores and compared for those patients screening positive and negative for bipolar disorder using the MDQ. The  20 Major depressive affective disorder single episode unspecified degree 296. 21 Major depressive affective disorder single episode mild degree 296. 22 Major depressive affective disorder single episode moderate degree 296. 23 Major depressive affective disorder single episode severe degree without psychotic behavior 296. 24 Major depressive affective disorder single episode severe degree specified as with psychotic behavior 296. 25 Major depressive affective disorder single episode in partial or unspecified remission 296. 26 Major depressive affective disorder single episode in full remission 296. 30 Major depressive affective disorder recurrent episode unspecified degree 296. 31 Major depressive affective disorder recurrent episode mild degree 296. 32 Major depressive affective disorder recurrent episode moderate degree 296. 33 Major depressive affective disorder recurrent episode severe degree without psychotic behavior 296. 34 Major depressive affective disorder recurrent episode severe degree specified as with psychotic behavior 296.35

Prevalence and Humanistic Impact of Potential Misdiagnosis of Bipolar Disorder Among Patients With Major Depressive Disorder in a Commercially Insured Population
Major depressive affective disorder recurrent episode in partial or unspecified remission 296.36 Major depressive affective disorder recurrent episode in full remission 311 Depressive disorder not elsewhere classified SDS item and summary scale scores were reported as the proportion of patients with "marked impairment" (score of 7-10 on a scale of 0-10).

Statistical Analysis
Demographic data and self-reported history were presented separately for the cohorts of patients who screened positive (MDQpositive) and negative (MDQ-negative) for bipolar disorder. Descriptive statistics were used to report continuous data and frequencies, and percentages were reported for categorical variables. SF-12 summary and item scores and productivity and absenteeism data from the SDS were compared using independent sample t-tests, and the percentages of patients with "marked impairment" in family, work, or social functioning domains as reported on the SDS were compared using Pearson chi-square tests. For all analyses, an a priori 2-tailed level of significance (alpha value) was set at the 0.05 level. Analyses were performed using STATA software version 8.2 (STATACorp., College Station, Texas).

■■ Results
A total of 41,738 patients from the claims database were identified as having MDD without bipolar disorder (Figure 1). Among the MDD-only patients with contact information, 5,777 patients (13.8%) were contacted for participation in the telephone survey; 4,417 (76.5%) of those (a) could not be reached due to no response to phone calls placed by survey interviewers, (b) did not reply to voicemail messages, or (c) refused participation. All patients who were asked in the screening process whether they had been told by a physician that they had depression answered affirmatively. The mean age for the 1,360 patients responding to the survey was 42.8 years (68.5% female); for nonrespondents, the mean age was 43.5 years (63.9% female) (data not shown). The age and gender distribution of the 1,360 patients completing the survey was similar to that of the overall 41,738 MDD patient population (mean age 43.1 years, 68.2% female) in our original study sample.  Prevalence and Humanistic Impact of Potential Misdiagnosis of Bipolar Disorder Among Patients With Major Depressive Disorder in a Commercially Insured Population who screened positive for bipolar disorder were much more likely than patients who screened negative to report symptoms of distraction, trouble concentrating, or trouble staying on track (92.6% vs. 45.2% of respondents, respectively, P < 0.001) and racing thoughts (86.2% vs. 40.2%, respectively, P < 0.001). The greatest differences between MDQ-positive and MDQ-negative patients in the proportion of patients responding positively were for the symptoms of feeling "hyper" (56.4% vs. 7.9%, respectively, P < 0.001) and "much more social or outgoing than usual" (60.6% vs. 8.9%, respectively, P < 0.001).

Prevalence of Bipolar Disorder
The prevalence of a MDQ-positive screen trended higher for men than for women (8.6% vs. 6.1%), but the difference was not statistically significant (P = 0.091). Prevalence was higher in patients aged between 18 and 45 years of age (8.5%) than in patients aged 46 years or older (4.8%, P = 0.007; Figure 2; Table 3).

SF-12
Thirty-three of 94 MDQ-positive respondents (35.1%) and 79 of 1,266 MDQ-negative respondents (6.2%) completed the SF-12 and SDS questionnaires. PCS and MCS scores (range 0-100, with higher scores representing better health) were compared between MDQ-positive and MDQ-negative cohorts (Figure 3). This analysis represented a point estimate of disease burden in terms of health status, with a recall period of the past 4 weeks. The 2 groups did not significantly differ on the PCS; however, patients with a positive screen for bipolar disorder had significantly lower mental health functioning as measured by the MCS (mean [SD] = 34.7 [11.7]) than did those with a negative screen (48.9 [10.8], P < 0.001). Among the individual domains or items, MDQpositive patients reported significantly worse performance on the social functioning and role emotional scales than did MDQnegative patients.

SDS
A significantly greater proportion of MDQ-positive patients reported marked impairment (score of 7 or higher on 10) in the 3 areas assessed than did MDQ-negative patients: work life (54.5% vs. 24.1%, respectively, P = 0.002), social life (66.7% vs. 39.2%, P = 0.008), and family life (66.7% vs. 34.2%, P = 0.002; Table 5) Additionally, in the 4 weeks before assessment, patients in the MDQ-positive cohort missed more than 6 times as many days of work (mean

■■ Discussion
This study evaluates the prevalence of potentially misdiagnosed bipolar disorder among a sample of patients with medical claims for MDD and the humanistic impact associated with misdiagnosis. Additionally, the study identified self-reported patient characteristics that were associated with potential misdiagnosis of bipolar disorder. Using the MDQ screening tool developed by Hirschfeld et al., [13][14][15] the overall proportion of patients screening positive for bipolar disorder was approximately 7%. This rate is similar to that reported in a study of 1,157 patients seeking primary care at an urban medicine clinic serving a low-income population, in which 10% screened positive on the MDQ for a lifetime history of bipolar disorder. 23 However, it is significantly lower than other prevalence reports in the literature, which range from 19% to 37%. 24 24 found a 37% rate of misdiagnosis in an outpatient psychiatric population. Prevalence estimates in primary care populations may yield lower rates than those in psychiatric populations. 25 Other causes of differences between the rates found in this study and other reported estimates include the use of a telephone survey rather than face-to-face diagnostic interviews, and the use of the MDQ screening tool as opposed to Structured Clinical Interview for DSM-IV (SCID).
It is well recognized that patients with bipolar disorder have diminished quality of life. 5,6,26,27 In this analysis, patients with potentially misdiagnosed bipolar disorder as assessed by the MDQ had significantly lower performance on the social functioning, Prevalence and Humanistic Impact of Potential Misdiagnosis of Bipolar Disorder Among Patients With Major Depressive Disorder in a Commercially Insured Population role emotional, and mental health scales of the SF-12, compared with MDQ-negative patients. In terms of personal interactions, our study findings indicate that a positive screen on the MDQ is associated with marked impairment in work, family, and social function. Results also suggest that patients screening positive for bipolar disorder on the MDQ are less likely to be married than MDQ-negative patients with MDD, and more likely to engage in high-risk behaviors.
The findings of this study are consistent with the findings reported by Calabrese et al., in that patients screening positive on the MDQ have more difficulties with work-related performance, social/leisure activities, and social/family interactions, compared with MDQ-negative patients. 28 Das et al. 23 reported that, in an urban clinic setting, patients screening positive on the MDQ had significantly lower mental health functioning as evaluated by the SF-12 and higher rates of marked depression-related impairment (a score greater than or equal to 7 on the subscales of the SDS) in their social and family life than did MDQ-negative patients. Our findings further strengthen the data presented in the literature on poor HRQOL and social functioning for patients screening positive on the MDQ.
Although this study did not evaluate burden of illness in terms of indirect costs, previous studies have documented the loss of productivity associated with bipolar disorder. 3,29 Gardner et al. found that employees with bipolar disorder missed 18.9 work days annually, compared with 7.4 days for employees without bipolar disorder. 30 Several published reports assessing costs of bipolar disorder and the economics of misdiagnosis suggest that misdiagnosis is associated with an increased direct and indirect cost burden. 11,17,[30][31][32][33] Although the patients screening positive on the MDQ in this study may encompass both bipolar I and bipolar II patients, it is noteworthy that a previous study found that mean 1-year allcause health care costs were nearly 4 times as high for patients with bipolar I disorder as for a comparison group of age-and sex-matched health plan members without a diagnosis of bipolar disorder ($7,663 vs. $1,962, respectively). 34 Rajagopalan et al. (2006) found significantly higher all-cause annual health care service costs in employees with bipolar disorder compared with employees with other mental disorders and estimated the annual all-cause health care costs for employees with bipolar disorder at $9,983, compared with $3,147 for a matched comparison group without bipolar disorder. 33 The poor humanistic outcomes in MDQ-positive patients in this study and the burden of illness associated with bipolar disorder reported in previous studies suggest that accurate and early diagnosis of bipolar disorder may result in improved patient outcomes.

Limitations
Although the combination of a claims-based analysis coupled with personal interviews of a large sample of MDD and bipolar disorder patients provides a unique source of data, this study has several limitations. First, the MDQ was used as the sole screening instrument for bipolar disorder, and the positive MDQ cases were not validated by the SCID diagnostic interview. The MDQ has been reported to have a sensitivity of 73% and a specificity of 90% in an outpatient clinical setting, 13 which suggests the occurrence of some false-positive screens in our study sample. Second, the 23.5% response rate to the telephone survey may raise concerns about nonresponse bias. However, a comparison of age and gender between respondents and nonrespondents indicated no meaningful differences between the groups on these characteristics. Third, the study design was retrospective, and the MDQ-positive cohort was populated using a quota sampling methodology. Causality cannot be ascribed in a study with a cross-sectional design, and the possibility exists that a factor other than bipolar disorder symptoms was the cause of the differences in outcomes.
Fourth, the use of administrative data also raises issues of coding accuracy and completeness, which may affect the results, and statistical differences in retrospective reviews reflect the quality of the data entered and abstracted from the database. Data updated through March 31, 2005, were used to conduct the survey in August 2005. During this time frame, patients with MDD may have been diagnosed with bipolar disorder, but due to a lag in claims processing, these patients may have been included in the MDD-only cohort of patients that were surveyed. Finally, the study excluded patients younger than 18 years of age, and bipolar disorder symptoms may appear in a large proportion of patients before age 15. 7 Despite the limitations, the present study provides evidence of the humanistic impact associated with potential misdiagnosis of bipolar disorder.

■■ Conclusion
The bipolar disorder misdiagnosis rate was 7% among managed care patients diagnosed with MDD. Patients with MDD who screened positive for undiagnosed bipolar disorder reported poorer scores on measures of mental health, role functioning, and depression-related disability scores than did patients who screened negative. Single marital status; lower self-reported income; a higher rate of high-risk behaviors; and poor social, family, and work functioning also were associated with an MDQpositive screen for bipolar disorder. Future research should focus on the development of clinically relevant predictors of bipolar disorder misdiagnoses that can help to identify high-risk patients.